The long-term objectives of our laboratory are to identify gene mutations that cause obesity in humans and to understand their pathogenic effects. This will provide a more rational approach to the therapy of human obesity. This research proposal focuses on the role of the G-protein coupled Melanocortin-4 Receptor (MC4R) in human obesity. We have shown that this gene is implicated in the first dominantly inherited form of common human obesity and that MC4R mutations cause obesity with a variable penetrance and expressivity. Our hypothesis is that differences in the functional alterations caused by obesity-associated MC4R mutations are the basis for the variable penetrance and expressivity of this genetic form of obesity. To further evaluate the overall role of MC4R in human obesity, to better understand the pathophysiology of human obesity-associated with MC4R mutations and to better evaluate the phenotype-genotype relationship within this form of obesity, we propose the following specific aims: 1) To compare the relative prevalence of different types of melanocortin-4 receptor mutations between large patient cohorts presenting with early or late onset severe obesity. 2) To extensively determine and to compare the nature of the functional alterations caused by the obesity-associated MC4R mutations found in these patient cohorts. 3) To determine if mutations in the MC4R promoter are implicated in human obesity. This study will provide new insights into the role of the MC4R gene in common obesity; promote new hypotheses for the molecular basis of common obesity, and open new avenues for the study of the basic function of MC4R, a major target for the treatment of human obesity.